Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively

Dunlop, Elaine A ORCID: https://orcid.org/0000-0002-9209-7561, Johnson, Charlotte ORCID: https://orcid.org/0000-0003-1954-5142, Wiltshire, Marie, Errington, Rachel Jane ORCID: https://orcid.org/0000-0002-8016-4376 and Tee, Andrew ORCID: https://orcid.org/0000-0002-5577-4631 2017. Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively. Oncotarget 10.18632/oncotarget.16232

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Abstract

Uncontrolled cell growth in Tuberous Sclerosis Complex occurs due to inappropriate activation of mechanistic (mammalian) target of rapamycin complex 1 (mTORC1). The current therapy, rapamycin, produced promising clinical trial results, but patient tumours regrow if treatment is discontinued, revealing rapamycin has cytostatic properties rather than a cytotoxic effect. Taking advantage of the enhanced levels of endoplasmic reticulum (ER) stress present in TSC2-null cells, we investigated drug combinations producing a cytotoxic response. We found a nelfinavir and salinomycin combination specifically killed TSC2-deficient, mTORC1 hyperactive cells. Cytotoxicity was rescued by reducing protein synthesis, either through mTORC1 inhibition or cycloheximide treatment. This indicates that the drug combination targets the cells by tipping the protein homeostasis balance of the already metabolically stressed TSC2-deficient cells in favour of cell death. Furthermore, this drug combination also inhibited tumour formation in TSC2-deficient cell models and caused tumour spheroid death in 3D culture. Importantly, the 3D assay could differentiate the cytostatic agent, rapamycin, from the cytotoxic nelfinavir/salinomycin combination. Sporadic cancer cell lines with hyperactive mTORC1 signalling were also susceptible to this nelfinavir/salinomycin drug combination. This work indicates that the protein homeostasis pathway is an attractive therapeutic target in both Tuberous Sclerosis Complex and mTORC1-driven sporadic cancers.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	mTORC1, TSC, therapy, nelfinavir, cell death
Publisher:	Impact Journals
ISSN:	1949-2553
Date of First Compliant Deposit:	17 March 2017
Date of Acceptance:	3 March 2017
Last Modified:	19 Jul 2024 20:07
URI:	https://orca.cardiff.ac.uk/id/eprint/98987

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